Telomeres, the ends of chromosomes, are essential for the stability and replication of eukaryotic chromosomes. See, e.g., Williamson J. R., Annu. Rev. Biophys. Biomol. Struct., 1994, 23:703. Telomeric sequences are shortened during cell division since DNA synthesis cannot fully replicate the extreme ends of chromosomes. A reduction in the telomere length to a critical level can lead to genomic instability, aberrant chromosome fusion, and cellular senescence. See, e.g., Harley et al., Curr. Opin. Genet. Dev., 1995, 5:249. In contrast, telomeres of tumor cells do not shorten during cell replication due to the presence of a telomerase, which allows adding nucleotides to telomeric DNA at the ends of chromosomes. See, e.g., Feng et al., Science, 1995, 269:1236. Telomerase is expressed in more than 85% of tumor cells, but not in most somatic cells. See Harley et al., Nature, 1990, 345:458. Thus, telomerase is becoming a promising target for cancer diagnosis and chemotherapy. See Blackburn E. H., Nature, 1991, 350:569.
Telomeres generally consist of many tandem repeats of guanine-rich (G-rich) motifs, such as T2AG3 in human telomeres. See Morin GB., Cell, 1989, 59:521. It is shown in in vitro assays that the 3′-overhang G-rich single strand adopts an intramolecular G-quadruplex structure. The quadruplex structure is stabilized by π-π interaction of a cyclic G-quartet, formed through Hoogsteen hydrogen bonding. See Gellert et al., Proc. Natl. Acad. Sci. USA, 1962, 48:2013. Since folding telomeric DNA into G-quadruplexes has been shown to inhibit telomerase activities in vitro, G-quadruplexes have also been considered as potential targets for antitumor agents. See Zahler et al., Nature, 1991, 350:718.